Point: Does the Risk of E-Cigarettes Exceed Potential Benefits? Yes

E-cigarettes are a gateway to smoking for young people; inadequate as cessation aid.

The use of e-cigarettes continues to dramatically increase, and the debate over their safety and appropriate use has heated up, in parallel. We as pulmonary clinicians are called upon to advise our patients and others about e-cigarettes, which presents challenges given the current limitations of the data upon which our advice should be based. What do we say?

At first glance the use of e-cigarettes appears to be an attractive option. Evaluation of the ingredients and particulates associated with e-cigarette vapors has demonstrated a substantial decrease in carcinogens compared with the traditional cigarette [1]. E-cigarettes can deliver nicotine in a form that is familiar to the traditional smoker, yet lacks many of the harmful constituents of cigarette smoke. The optimist envisions a cohort of multi-pack year smokers switching to the e-cigarette with a resultant rapid decrease in risks of heart disease, chronic lung disease, and cancer. But is this optimism justified by empiric evidence of safety, and favorable data on patterns of use, or is this simply wishful thinking?

Too often in the debate about the e-cigarette the focus is upon the relative lack of proof of harm and the flawed assumption that lack of evidence of harm equals evidence of safety. This is the wrong perspective. Instead, the focus needs to be upon proof that e-cigarettes are safe (alone or in conjunction with active smoking, since many are dual users), that they are effective in accomplishing some good (smoking reduction or cessation), and that they don't promote an increase in the population of nicotine-addicted individuals. At present we lack such proof.

E-cigarettes as a Gateway to the Traditional Cigarette

Most defenders of e-cigarette use base their perspective on the concept of harm-reduction, and the assumption that the only users of e-cigarettes are or will be current tobacco smokers looking for a safer cigarette. One of the early concerns with the e-cigarette, however, was that it might introduce young, nontobacco users to nicotine addiction, and there is recent evidence to support the validity of that concern. A recent cross-sectional survey-based study reported on trends of e-cigarette use from 2010 through 2013. E-cigarette use increased dramatically over this interval. The highest prevalence of use was among very young adults, ages 18-25. A third of current e-cigarette users were nonsmokers and 1.4% were never-smokers[2].

The trend toward younger groups being aware of and using e-cigarettes is also on the rise. A survey of 4,780 middle school and high school students from Connecticut identified a high rate of awareness, as well current and lifetime use, of e-cigarettes among those students 3. Additionally, a study that sought to gauge "openness" to starting tobacco products identified the use of e-cigarettes as a significant factor in being likely to try tobacco products in the future [4].

What all of these studies tell us collectively is that the cohort of e-cigarette users is growing, young, and open to using both e-cigarettes and traditional tobacco products -- not a group of seasoned smokers trying to quit or looking for an alternative to the traditional cigarette. The e-cigarette may well contribute to an overall increase in nicotine addiction.

E-cigarettes as a Cessation Aide

E-cigarettes have not been marketed as cessation aids (as doing so would have implications for FDA regulation) but have been advocated for this purpose, and many smokers have purchased these products as a way to stop smoking. Despite anecdotal reports that suggest effectiveness, there is not good evidence to suggest that e-cigarettes are superior to traditional, FDA-approved approaches to smoking cessation.

Caponnetto et al. conducted a clinical study of ENDS devices in cigarette smokers not intending to quit as an extension of their previous nonrandomized pilot study [5]. The investigators randomized 300 subjects to one of three arms then followed subjects for eight visits over 52 weeks to assess for ≥50% reduction in smoking, abstinence, and adverse events. The groups were: a) 12-weeks of 7.2 mg nicotine e-cigarettes; b) 6-weeks of 7.2 mg nicotine followed by 6-weeks of 5.4 mg nicotine e-cigarettes; and c) 12-weeks of placebo e-cigarettes which looked like the nicotine-containing e-cigarettes but contained only the carrier liquid. Under the intention-to-treat analysis, there were no significant differences between the groups in terms of cessation rates or reduction in the number of cigarettes smoked at 52 weeks.

Bullen et al. conducted a pragmatic randomized controlled trial to assess the efficacy of e-cigarettes for smoking cessation compared with nicotine replacement therapy [6]: 657 smokers desiring to quit were randomized to receive 16 mg e-cigarettes, 21 mg nicotine patches daily, or placebo e-cigarettes in a 4:4:1 ratio. Though at 1 month there was a significant difference in continuous abstinence favoring e-cigarettes (relative risk [RR] 1.46 [95% CI, 1.04-2.04]), this difference did not persist at 3 and 6 months. Given inadequate safety data and other concerns, and lack of evidence of superior efficacy, we would be remiss in recommending e-cigarettes over other approaches to smoking cessation.

Direct Toxic Effects of E-cigarettes

Multiple studies have reported on the toxicities that are associated with e-cigarette use. These studies have established that e-cigarettes are associated with increased nausea, vomiting, headache, choking, and upper airway irritation [7]. One study demonstrated that after only 5 minutes of smoking an e-cigarette, subjects' airway resistance significantly increased from baseline. In these same individuals exhaled FeNO was also decreased indicating that after only 5 minutes of exposure there was a significant change in the biologic function of the lung.

Marini et al. went on to show that the effects on NO synthesis by the lung were similar between e-cigarettes and traditional cigarettes [8] . Using an animal model of asthma, researchers have established that e-cigarettes exacerbate the basic biology that drives asthmatic symptoms by increasing the influx of eosinophils into the airway and increasing synthesis of IL-4, IL-5, IL-13 and IgE [9].

Perhaps most concerning is recent data that have established that e-cigarettes can alter gene expression in bronchial epithelial cells, leading to a higher malignant transformation, in a similar way to traditional cigarettes [10]. The early evidence for the toxic effect of e-cigarettes is clear; they are an irritant to the airway and they have direct effects on gene expression and protein synthesis that promote airway inflammation and potential malignant transformation.

Conclusion

There is no evidence that e-cigarettes are safe and there is some evidence that they may in fact be harmful, both through introducing new young users to nicotine addiction, and through direct effects upon the lung. It took decades for the medical community to recognize, prove, and accept that cigarettes are a major health hazard; we should not make the same error with e-cigarettes. We risk losing hard-won ground in the battle on smoking through the so-called 'renormalization' of smoking that may attend the uncritical acceptance of e-cigarettes, and that is a stated goal of the e-cigarette industry [11].

Additional research to fully understand the health effects of e-cigarettes, including among dual users of e-cigarettes and traditional cigarettes, is needed. Harm-reduction arguments are only valid if we can objectively document an overall reduction in harm, at both the individual and population levels, and at present we cannot.

When patients come to us and ask for guidance about the use of e-cigarettes, they are expecting a response informed by data. The limited data we have at present does not demonstrate benefits exceeding known risks.

Mark V. Avdalovic, MD, MAS, FCCP,is Associate Professor of Clinical Medicine in the Division of Pulmonary, Critical Care and Sleep medicine at the University of California Davis School of Medicine. He obtained his medical degree from the Medical College of Wisconsin and completed residency and fellowship training at the UC Davis Medical Center. He has clinical and research interests in COPD and Pulmonary Hypertension, he leads a translational science research group focused on the study of angiogenesis in the lung. He and his colleagues recently identified an effect of maternal nicotine exposure on fetal lung development. He is also part of a Quality Improvement grant focused on using the electronic health record to help identify active smokers and steer them toward cessation programs.

Susan Murin, MD, MSc, is Professor of Clinical Internal Medicine in the Division of Pulmonary and Critical Care and Sleep Medicine, and Vice-Chair of the Department of Internal Medicine, at UC Davis School of Medicine. She completed her training in Pulmonary and Critical Care Medicine at Yale University School of Medicine and received her Masters in Clinical Epidemiology from the Harvard School of Public Health and MBA from the UC Davis Graduate School of Management. She has been on the faculty at UC Davis School of Medicine since 1995. Her clinical and research interests include smoking and the lung and venous thromboembolism. She is active in numerous professional organizations including the ACCP.

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